1. Field of the Invention
The present invention relates to a method of improving ovulation induction and embryo quality in women undergoing in vitro fertilization and other infertility treatments involving administering an androgen such as dehydroepiandrosterone prior to or during ovulation stimulation cycles.
2. Description of the Related Art
The application of assisted reproductive technology has revolutionized the treatment of all forms of infertility. The most common assisted reproductive technology is in vitro fertilization (IVF), in which a woman's eggs are harvested and fertilized with a man's sperm in a laboratory. Embryos grown from the sperm and eggs are then chosen to be transferred into the woman's uterus. Assisted reproductive technology in women depends on ovarian stimulation and concurrent multiple oocyte development, induced by exogenous gonadotropins.
Infertile women are often treated with gonadotropin treatments such as gonadotropin-releasing hormone (GnRH) flare protocols. Estrogen pre-treatment with concomitant growth hormone (GH) treatment is sometimes used in an effort to try and amplify intra-ovarian insulin-like growth factor-I (IGF-I) paracrine effect, which is expressed by granulosa cells and enhances gonadotropin action. However, the clinical utility of combined GH/ovarian stimulation is limited and responses are not dramatic.
Dehydroepiandrosterone (DHEA) is secreted by the adrenal cortex, central nervous system and the ovarian theca cells and is converted in peripheral tissue to more active forms of androgen or estrogen. DHEA secretion during childhood is minimal but it increases at adrenarche and peaks around age 25, the age of maximum fertility, only to reach a nadir after age 60. There is evidence to support use of exogenous DHEA to increase ovulation stimulation in older women who respond poorly to gonadotropin treatments. First, studies demonstrate marked augmentation of serum IGF-I concentrations of oral administration of physiological DHEA. Second, DHEA is a steroid prohormone for ovarian follicular sex steroidogenesis.
Third, Casson studies have shown that concurrent oral DHEA supplementation over about two months and one or two stimulation cycles improved gonadotropin response by approximately two-fold in women who had normal follicular stimulating hormone concentrations, yet had poor response to ovarian stimulation. Frattarelli and Peterson found that cycle day 3 testosterone above 20 ng/dL was associated with higher IVF pregnancy rates (11.2% vs. 53.1%). Approximately 25 to 50 mg of DHEA is considered physiologic replacement for young females. Adverse effects are extremely uncommon at such dosages, while dosages as high as 1600 mg daily have caused significant side effects, requiring discontinuation of treatment.
The “aging ovary” represents the last frontier of human infertility treatment and is generally considered untreatable with current medical resources. The possibility that any intervention may significantly benefit the response of the aging ovary is therefore potentially revolutionary. The studies show many ways in which ovulation induction can be improved in infertile women. These studies show DHEA as possible, but not preferred, treatments for improving ovulation induction.